Absorbable, permeability-modulated barrier composites and applications thereof

ABSTRACT

Absorbable barrier composites are designed for modulated gas and water permeability depending on clinical use and are formed of at least two physicochemically distinct components, one of which is a film adjoined to a knitted mesh and/or electrostatically spun, non-woven fabric. Depending on the physicochemical properties of the barrier composite, it can be used in neurological and urinogenital surgical procedures as well as tissue engineering and/or as physical barriers to prevent adhesion formation following several types of surgical procedures.

FIELD OF THE INVENTION

This invention is directed to absorbable barrier composites withmodulated gas and water permeability, the composite formed of a flexiblefilm and at least one fibrous or microfibrous adjoining component in theform of knitted mesh or electrospun, non-woven fabric, respectively.These composites can be tailored to allow their use in neurological andurinogenital procedures and particularly those associated with spine,cranial and urinary bladder prostheses. Due to their flexibility andbarrier properties, these composites are suitable for use in theprevention of adhesion formation following several types of surgicalprocedures.

BACKGROUND OF THE INVENTION

The use of sutures and meshes made from absorbable polymers has beendisclosed in numerous patents for the past four decades. However, overthe past three decades, the use of absorbable fibers in fibrouscomposites has been limited for the most part to bicomponent compositesfor use in (1) solid fiber-reinforced orthopedic devices, and to alesser extent, (2) synthetic absorbable vascular grafts. Availability ofnew types of fiber-forming and microfiber-forming absorbable polymersled to the development, in this laboratory, of a number of fibrous andmicrofibrous medical constructs having a broad range of properties.These include (1) fully or partially absorbable composites forurological and vascular applications [U.S. Pat. No. 7,371,256 (2002);U.S. patent application Ser. No. 10/860,677 (2003); U.S. patentapplication Ser. No. 11/175,635 (2005); U.S. patent application Ser. No.11/204,822 (2005); and U.S. patent application Ser. No. 11/346,117(2006)], and fully or selectively absorbable knitted meshes [U.S. patentapplication Ser. No. 11/886,370 (2007); U.S. patent application Ser. No.11/978,795 (2007); U.S. patent application Ser. No. 11/983,321 (2007)].However, none of these composites was claimed as havingpermeability-modulated barrier properties to allow their application asmedical devices or components thereof for use in conjunction with thesurgical procedures noted in the present invention. Most important amongsuch procedures are those dealing with prosthetic dura mater and patchesfor repairing the urinary bladder and vascular tissue and/or theirtissue engineering. Accounts of the prior art related to the area aredescribed below.

In a disclosure on bladder reconstruction that is pertinent to theinstant invention (U.S. Pat. No. 6,576,019) the inventor provided auseful background to his invention, excerpts of which are summarizedbelow:

The human urinary bladder is a musculomembranous sac situated in theanterior part of the pelvic cavity and serves as a reservoir for urine,which it receives through the ureters and discharges through theurethra. The bladder ureters and urethra are all similarly structured inthat they comprise muscular structures lined with a membrane comprisingurothelial cells coated with mucus that is impermeable to the normalsoluble substances of the urine. The bladder tissue is elastic andcompliant. That is, the bladder changes shape and size according to theamount of urine it contains. A bladder resembles a deflated balloon whenempty but becomes somewhat pear-shaped and rises in the abdominal cavitywhen the amount of urine increases.

The bladder wall has three main layers of tissues: the mucosa,submucosa, and detrusor. The mucosa, comprising urothelial cells, is theinnermost layer. The submucosa lies immediately beneath the mucosa andits basement membrane. It is composed of blood vessels which supply themucosa with nutrients and the lymph nodes which aid in the removal ofwaste products. The detrusor is a layer of smooth muscle cells whichexpands to store urine and contracts to expel urine. The bladder issubjected to numerous maladies and injuries which cause deteriorationwhich may result from infectious diseases, neoplasms and developmentalabnormalities. Further, bladder deterioration may also occur as a resultof trauma such as, for example, car accidents and sports injury.

Although a large number of biomaterials, including synthetic andnaturally derived polymers, have been employed for tissue reconstructionor augmentation, no material has proven satisfactory for use in bladderreconstruction. For example, synthetic biomaterials such as polyvinyland gelatin sponges, polytetrafluoroethylene, and silastic patches havebeen relatively unsuccessful, generally due to foreign body reactions.Other attempts have usually failed due to mechanical, structural,functional, or biocompatibility problems. Permanent synthetic materialshave been associated with mechanical failure and calculus formation.Naturally derived materials such as lyophilized dura, deepithelializedbowel segments, and small intestinal submucosa have also been proposedfor bladder replacement. However, it has been reported that bladdersaugmented with dura, peritoneum placenta, and fascia contract over time.

In an effort to circumvent the drawbacks of the prior art disclosed in,Atala, U.S. Pat. No. 6,576,019 (2003) a device comprising abiocompatible synthetic or natural polymeric matrix shaped to conform toat least a part of the luminal organ or tissue structure with a firstcell population on or in a first area and a second cell population suchas a smooth muscle cell population in a second area of the polymericmatrix. The method involves grafting the device to an area in a patientin need of treatment. The polymeric matrix comprises a biocompatible andbiodegradable material.

In a second disclosure pertinent to the instant invention on artificialdura mater, Yamauchi et al. [U.S. Pat. No. 7,041,713 (2006)] provided auseful background to the subject of this invention, excerpts of whichare summarized below with necessary editing to facilitate readability.

The dura mater is located between the cranium and the brain and aroundthe spinal cord. It principally protects the brain and spinal cord andprevents cerebrospinal fluid leakage. Defects or contractures of thedura mater need to be compensated for and lyophilized human dura materhas been used for that purpose. However, human dura mater has drawbackssuch as low homogeneity and limited supply. Further, possibletransmission of Creutzfeldt-Jakob disease through the use of human duramater has been reported. To solve the above noted problems, anartificial dura mater made of silicone was developed. However, siliconedura mater has fallen into disuse as it was reported that silicone duramater creates a predisposition to meningorrhagia by remainingpermanently in vivo because it is non-biodegradable, chronicallystimulating the surrounding tissue and causing hypertrophy of thegranulation tissue. In contrast, artificial dura maters made ofbiodegradable and bioabsorbable materials such as collagen were producedbut they are not in practical use because of strength-related problems,i.e., because their suture strength is insufficient to allow them to besutured integrally with the dura mater.

This led Yamauchi et al [U.S. Pat. No. 7,041,713 (2006)] to conceive anartificial dura mater, which comprises an amorphous or low crystallinitypolymer as a constituent component and which prevents the cerebrospinalfluid leakage. More specifically, these inventors described a method forpreparing an artificial dura mater which is formed as an integralmolding of an amorphous or low crystallinity polymer and a structuralreinforcement wherein the amorphous or low crystallinity polymer and thestructural reinforcement are integrated by bonding, fusion orimpregnation, the amorphous or low crystallinity polymer having (1) adegree of crystallinity of 20 percent or lower; (2) an elastic modulusat 4 percent extension of 10 MPa or lower; (3) a T_(g) of 15° C. orlower; (4) a tensile elongation at break of 200 percent or greater; (5)an elastic modulus at 37° C. of 1×10⁸ Pa or less; and (6) a ratio ofrelaxation elastic modulus at 23° C./elastic modulus at 37° C. of 0.3 orgreater. Meanwhile, the structural reinforcement was described as having(1) an elastic modulus at 5 percent extension of greater than 10 MPa;(2) a T_(g) of higher than 15° C.; and (3) a tensile elongation at breakof less than 200 percent. Furthermore, the amorphous or lowcrystallinity polymer was noted as having a weight of 10 to 98 percentof the total weight of the integral molding, and the structuralreinforcement having a weight of 2 percent or more of the total weightof the integral molding. The method of preparing said artificial duracomprises the step of integrating the amorphous or low crystallinitypolymer and the structural reinforcement by bonding, fusing orimpregnating to give an integrally molded artificial dura mater.

In a disclosure of general pertinence to the present invention on pelvicfloor construction, Tripp et al. [U.S. Pat. No. 6,197,036 (2001)],provided a background to their invention, excerpts of which appearbelow.

Damage to the pelvic floor is a serious medical condition which mayoccur during delivery or due to injury to the vesicovaginal fascia. Suchan injury can result in a herniation of the bladder called a cystocele.Other similar conditions are known as rectoceles, enteroceles, andenterocystoceles. A rectocele is a herniation of the rectum. Anenterocele is formed when the intestine protrudes through a defect inthe rectovaginal or vesicovaginal pouch and an enterocystocele is adouble hernia in which both the bladder and the intestine protrude.These herniations are serious medical problems that can severely andnegatively impact a patient both physiologically and psychologically.Treatment of these conditions requires repositioning of the protrudingorgans or portions thereof. Existing tissue is often compromisedfacilitating the need to use a synthetic patch. Current medicalprocedures for repositioning the protruding organs or portions thereofmay be time consuming or invasive. Hence, there is a need for reducingthe amount of time which these procedures require and the invasivenessof the procedures. Accordingly, Tripp et al (U.S. Pat. No. 6,197,036(2001)) disclosed that herniation, including cystocele, rectocele, andenterocystocele may be treated with prefabricated repair patches. Therepair patches include a natural or synthetic biocompatible materialhaving a shape adapted to support herniated tissue. The patch alsocontains a plurality of apertures positioned in the central plane of thepatch which may permit ingrowth and may also be an attachment site forfixing sutures. The patch may be covered with coating to decrease thepossibility of infection, and/or increase biocompatibility. The coatingmay also include one or more drugs, for example, an antibiotic, animmunosuppressant, and/or an anticoagulant.

In a second disclosure of general pertinence to the present invention onthe use of reinforced foam implants with enhanced integrity for softtissue repair and regeneration, Binette et al. [U.S. Pat. No. 6,884,428(2005)] described a biocompatible tissue repair stimulating implant or“scaffold” device that is used to repair tissue injuries, particularlyinjuries to ligaments, tendons, and nerves. Such implants are especiallyuseful in methods that involve surgical procedures to repair injuries toligament, tendon, and nerve tissue in the hand and foot. The repairprocedures may be conducted with implants that contain a biologicalcomponent that assists in healing or tissue repair.

Reviewing the above noted disclosures of the prior art show clearly theabsence of any absorbable permeability-modulated barrier composites andtheir use as novel prosthetic devices or for the prevention of adhesionformation. This provided an incentive to explore the new featuresassociated with the instant invention.

SUMMARY OF THE INVENTION

This invention deals with an absorbable, permeability-modulated barriercomposite of at least two physicochemically distinct components, whereinone of the components is a flexible film having a thickness of less thanabout 500. In a preferred embodiment, the flexible film has a thicknessof less than about 200 microns and is adjoined directly to anelectrostatically spun, non-woven microfibrous fabric, wherein theflexible film is made of (1) a polyaxial copolyester derived from atleast two monomers selected from the group consisting of glycolide,l-lactide, ε-caprolactone, trimethylene carbonate, p-dioxanone,1,5-dioxepan-2-one, and a morpholinedione, (2) a polyether-ester derivedfrom a polyether-glycol grafted with at least one monomer selected fromthe group consisting of glycolide, l-lactide, ε-caprolactone,trimethylene carbonate, p-dioxanone, 1,5-dioxepan-2-one, and amorpholinedione, or (3) a polyether-ester-urethane derived from apolyether-glycol grafted with at least one monomer selected from thegroup consisting of glycolide, l-lactide, ε-caprolactone, trimethylenecarbonate, p-dioxanone, 1,5-dioxepan-2-one, and a morpholinedione—theresulting chains of the polyether-ester-glycol are interconnected byurethane linkages formed through the reaction of saidpolyether-ester-glycol with an aliphatic diisocyanate. Theelectrostatically spun, non-woven fabric is made of a polyaxialcopolyester derived from at least two monomers selected from the groupconsisting of glycolide, l-lactide, ε-caprolactone, trimethylenecarbonate, p-dioxanone, 1,5-dioxepan-2-one, and a morpholinedione.Alternatively, the electrostatically spun, non-woven fabric is made of apolyether-ester derived from a polyether-glycol grafted with at leastone monomer selected from the group consisting of glycolide, l-lactide,ε-caprolactone, trimethylene carbonate, p-dioxanone, 1,5-dioxepan-2-one,and a morpholinedione.

From a clinical perspective, the instant invention deals with anabsorbable, permeability-modulated barrier composite for application asa dura mater prosthesis for use in spinal and cranial surgicalprocedures as well as for applications dealing with preventing adhesionformation following abdominal and urinogenital surgical procedures.

A specific aspect of this invention deals with an absorbable,permeability-modulated barrier composite of at least twophysicochemically distinct components, wherein one component is aflexible film having a thickness of less than about 400 microns, whichis adjoined directly to a knitted mesh and indirectly to anelectrostatically spun, non-woven microfibrous fabric, wherein theflexible film is made of a (1) polyaxial copolyester derived from atleast two monomers selected from the group consisting of glycolide,l-lactide, ε-caprolactone, trimethylene carbonate, p-dioxanone,1,5-dioxepan-2-one, and a morpholinedione, (2) polyether-ester derivedfrom a polyether-glycol grafted with at least one monomer selected fromthe group consisting of glycolide, l-lactide, ε-caprolactone,trimethylene carbonate, p-dioxanone, 1,5-dioxepan-2-one, and amorpholinedione, or (3) polyether-ester-urethane derived from apolyether-glycol grafted with at least one monomer selected from thegroup consisting of glycolide, l-lactide, ε-caprolactone, trimethylenecarbonate, p-dioxanone, 1,5-dioxepan-2-one, and a morpholinedione—theresulting chains of the polyether-ester-glycol are interconnected byurethane linkages formed through the reaction of saidpolyether-ester-glycol with an aliphatic diisocyanate. Theelectrostatically spun, non-woven fabric is made of a polyaxialcopolyester derived from at least two monomers selected from the groupconsisting of glycolide, l-lactide, ε-caprolactone, trimethylenecarbonate, p-dioxanone, 1,5-dioxepan-2-one, and a morpholinedione.Alternatively, the electrostatically spun, non-woven fabric is made of apolyether-ester derived from a polyether-glycol grafted with at leastone monomer selected from the group consisting of glycolide, l-lactide,ε-caprolactone, trimethylene carbonate, p-dioxanone, 1,5-dioxepan-2-one,and a morpholinedione.

A special aspect of this invention deals with an absorbable,permeability-modulated barrier composite of at least twophysicochemically distinct components, wherein one component is aflexible film having a thickness of less than about 400 microns, whichis adjoined directly to a knitted mesh and indirectly to anelectrostatically spun, non-woven microfibrous fabric, wherein theknitted mesh is of a warp-knitted construction and is made of apolyaxial copolyester derived from at least two monomers selected fromthe group consisting of glycolide, l-lactide, ε-caprolactone,trimethylene carbonate, p-dioxanone, 1,5-dioxepan-2-one, and amorpholinedione. Alternatively, the knitted mesh is of a warp-knittedconstruction and is made of a polyether-ester derived from apolyether-glycol grafted with one monomer selected from the groupconsisting of glycolide, l-lactide, ε-caprolactone, trimethylenecarbonate, p-dioxanone, 1,5-dioxepan-2-one, and a morpholinedione.

A key clinical aspect of this invention deals with an absorbable,permeability-modulated barrier composite of at least twophysicochemically distinct components, wherein one component is aflexible film having a thickness of less than about 400 microns, whichis adjoined directly to a knitted mesh and indirectly to anelectrostatically spun, non-woven microfibrous fabric, wherein saidcomposite is constructed to be used as a patch for repairing orreplacing part of the urinary bladder of a vertebrate animal and/or as avascular patch for repairing or replacing part of a blood vessel of avertebrate animal.

Another special aspect of this invention deals with an absorbable,permeability-modulated barrier composite of at least twophysicochemically distinct components, wherein one component is aflexible film having a thickness of less than about 500 microns, whereinat least one of its components comprises at least one bioactive agentselected from the group consisting of antimicrobial agents, anestheticagents, anti-inflammatory agents, and tissue growth-promoting agents.

An important aspect of the instant invention deals with an absorbable,permeability-modulated barrier composite of at least twophysicochemically distinct components, wherein one component is aflexible film having a thickness of less than about 500 microns, whereinat least one of its components comprises a hydroswellable polymer, andwherein at least one of its components comprises at least one bioactiveagent selected from the group consisting of antimicrobial agents,anesthetic agents, anti-inflammatory agents, and tissue growth-promotingagents.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention generally is directed to absorbable barriercomposite constructs, with modulated gas and water permeability, made ofa flexible film and at least one fibrous or microfibrous adjoiningcomponent in the form of knitted multifilament yarn or electrospunmicrofibrous, non-woven fabric, respectively. Depending on types ofpolymeric materials used to produce the individual components of thecomposite and the mode of constructing these components individually orin different combinations to assemble the final form of the composites,they can be used in a variety of applications in conjunction withseveral types of surgical procedures. These can be associated withrepair, replacement or tissue engineering of components of the digestivetract, respiratory system, neurological tissues, bone, cartilage,urinary tract, genital tract, vascular system and skin. More specificapplications entail the use of the composites in plastic surgery,repairing hernial defects at different body sites, and preventing orminimizing adhesion formation following several types of surgicalprocedures.

Towards constructing barrier composites having a wide range ofproperties and applicability, chemical structure is one of the basicvariables that can be controlled to modulate the properties of thedifferent components of the composites. Accordingly, the polymericmaterials can be (1) made of absorbable chains having variablehydrolytic stability by virtue of the type of ester linkages present inthe macromolecular chain; (2) made of absorbablepolyether-ester-urethane having a range absorption profile, mechanicalcompliance and hydroswellability—the hydroswellability allows thematerial to soften and controllably release any bioactive agent thereinupon contacting water in the biological environment and to be morecompliant and mechanically compatible with different types of softtissues; and (3) based on copolymeric chains wherein the constituentrepeat units are present in a random fashion or segmented and blockarrangements. The mode of conversion of the different polymers to thedesirable forms is another basic variable that can be controlled tomodulate the physico-mechanical properties of the individual componentsand their performance in the final composite construct. These variablesentail those related to (1) fiber formation and fiber processing toknitted mesh; (2) electrospinning, and method of adjoining themicrofibrous fabric to other construct components; and (3) filmformation and method for adjoining to other construct components.

This invention also deals with controlling the variables discussed aboveto allow the use of the barrier composites in different applicationsassociated with several types of surgical procedures. Some of the usefulapplications of the barrier composites of the instant invention entail(1) the use of a bicomponent or tricomponent composite comprising aflexible film adjoined to a microfibrous non-woven fabric or a filmadjoined directly to a knitted mesh that is, in turn, adjoined to amicrofibrous, non-woven fabric, respectively, as dura substituteswherein the film prevents leakage, the microfibrous fabric is toaccelerate tissue ingrowth and mechanical anchoring, and, if so needed,the knitted mesh provides needed mechanical strength—these are expectedto provide immediate restitution of a membranous covering for the brainwithout inducing any adverse reaction in the host or provoking adhesionto underlying nervous tissue and ideally to absorb and be replaced bytissues similar to the dura mater; (2) the use of a three-componentcomposite as in item 1 in laparoscopic paraesophageal, hernia, andanterior vaginal wall repairs; (3) the use of a two- or three-componentcomposite as in item 1 in spinal surgery repair, wherein at least one ofthe components is hydroswellable—the use of a synthetic dura prosthesismade of a barrier composite that softens in the biological environment,prevents leakage of the cerebrospinal fluid and post-surgicalcomplications, which increase the patient risk to meningitis andarachnoiditis; and (4) the use of the three-component barrier compositedescribed in item 1 as a patch for repairing or tissue engineeringspecific sites in the gastrointestinal tract, blood vessels,urinogenital tract, and especially the urinary bladder.

Additional illustrations of this invention are provided in the followingexamples.

Example 1 Synthesis and Characterization of a Typical Film-Forming,Absorbable, Polyaxial, Segmented Copolyester of Glycolide, TrimethyleneCarbonate, and ε-Caprolactone, P1

The first step for preparing P1 entailed the preparation of apolytrimethylene carbonate polymeric initiator (PPI-1). This wasprepared by the ring-opening polymerization of trimethylene carbonate(TMC, 16 g, 0.157 mole) in the presence of trimethylolpropane (TMP) asthe initiator at a monomer/initiator ratio of 15 and stannous octanoate(SnOct) as the catalyst at a monomer/catalyst ratio of 10,000. Thepolymerization was conducted under dry nitrogen in a predried resinkettle equipped for mechanical stirring. The polymerization of TMC wasachieved by heating the reaction mixture at 160° C. and keeping it atthat temperature until an essentially complete monomer conversion wasrealized (as determined by GPC); this took about 1.5 hours. In thesecond step towards preparing P1, the PPI-1 was mixed in the samereaction vessel with glycolide (551.7 g, 4.7556 moles) andε-caprolactone (232.3 g, 2.038 moles). The reaction mixture was heatedto 95° C. to melt the glycolide. The liquid reaction mixture was stirredfor 15 minutes at 95° C. prior to adding additional amounts of catalystto achieve an overall monomer/catalyst ratio of about 32634. Thereaction temperature was raised to 180° C. and the polymerization wascontinued at this temperature for 7 hours; the stirring was maintaineduntil the product became too viscous to stir. At the conclusion of thepolymerization, the product was cooled, isolated, and ground. The groundpolymer was dried and residual monomer was removed by distillation underreduced pressure. The purified polymer was characterized for molecularweight in terms of inherent viscosity (I.V.) in hexafluoroisopropylalcohol (HFIP), and thermal properties by differential scanningcalorimetry (DSC) and was shown to have an I.V. in HFIP=1.4 dL/g, and amajor melting temperature (T_(m))=215° C.

Example 2 Synthesis and Characterization of a Typical Film-Forming,Absorbable, Segmented Polyether-Ester of Polyethylene Glycol Linked to aHigh-Glycolide Copolymeric Segment, P2

A polymerization reactor similar to that described in Example 1 was usedto prepare P2 by reacting predried polyethylene glycol having amolecular weight of 20 kDa (PEG-20K, 48 g, 0.0024 mole) with a mixtureof glycolide (698.5 g, 6.0223 mole) and trimethylene carbonate (53.41g., 0.523 mole) in the presence of stannous octanoate as catalyst at amolar monomer/catalyst ratio of 14×10³. The polymerization schemeentailed first transferring the PEG-20K into the reactor and heating itunder reduced pressure at 140° C. for about 30 minutes. The PEG-20K wasthen cooled to 95° C. and a mixture of the monomers and catalyst wasadded and stirred until a liquid mixture was obtained. The reactiontemperature was raised to 180° C. and polymerization was continued atthis temperature. Stirring of the polymerizing system was maintaineduntil the product became too viscous to stir, and the reaction was thencontinued for 6 hours. At the conclusion of the polymerization, theproduct was isolated, purified, and characterized as discussed inExample 1. The purified polymer was shown to have an I.V. in HFIP=1.5dL/g and T_(m)=223° C.

Example 3 Synthesis and Characterization of a TypicalMicrofiber-Forming, Absorbable Polyaxial, High-Lactide, SegmentedCopolyester, P3

Following a similar procedure to that described in U.S. Pat. No.6,462,169, a triaxial polymeric initiator was made using 35/14/17(molar) ε-caprolactone (CL)/trimethylene carbonate (TMC)/glycolide (G)and then end-grafted with 34/8 (molar) l-lactide (L)/glycolide.Accordingly, the polymeric initiator was prepared by the ring-openingpolymerization of CL (227.3 g, 1.9941 mole), TMC (81.4 g, 0.7977 mole),and G (59.5 g, 0.5128 mole) in the presence of triethanolamine (1.0559g, 7.0865×10⁻³ mole) and stannous octanoate (41.1 mg, 1.0211×10⁻⁴ mole)as the initiator and catalyst, respectively. The polymerization wasachieved by heating at 180° C. for 3 hours. The resulting polymericinitiator was cooled to 150° C. and then mixed under nitrogen withl-lactide (279.0 g, 1.9372 mole) and glycolide (52.9 g, 0.4558 mole) andan additional amount of stannous octanoate (41.1 mg, 1.0211×10⁻⁴ mole).The system was stirred while heating to 190-200° C. to achieve a uniformmelt. The temperature was then lowered to 140° C. and the reaction wascontinued without stirring for 24 hours. The polymer was isolated,ground, dried, and heated under reduced pressure to remove unreactedmonomer. The polymer was characterized by IR and NMR (for identity),thermal transition (T_(m)=109° C.), and I.V. in chloroform (I.V.=1.4dL/g).

Example 4 Synthesis and Characterization of a TypicalMicrofiber-Forming, Absorbable, Segmented Polyether-Ester ofPolyethylene-Glycol Linked to High-Lactide Copolymeric Segments, P4

Predried crystalline, high molecular weight PEG (M_(w)=12 kDa, 30 g,0.0025 mole) was mixed, under nitrogen in a stainless steel reactorequipped for mechanical stirring, with a mixture of l-lactide (604.2 g,4.1958 mole) and TMC (17.8 g, 0.1743 mole) in the presence of stannousoctanoate (1.9 g, 0.0163 mole) as a catalyst. The mixture was thenheated to achieve complete dissolution of all reactants. The mixing wascontinued while heating to a polymerization temperature of 140° C. Thereaction was maintained at that temperature while stirring until theproduct became too viscous to stir and essentially complete monomerconversion was achieved (60 hours). At this stage, the reaction wasdiscontinued, the product was cooled, isolated, ground, dried, andtraces of residual monomer were removed by distillation under reducedpressure. The purified polymer was characterized from molecular weight(by GPC), I.V., and thermal transition (by DSC) and shown to have aM_(n)=110 kDa, I.V.=1.8 dL/g, and T_(m)=180° C.

Example 5 Synthesis and Characterization of a Typical Fiber-Forming,Segmented Polyaxial, High-Glycolide Copolyester, P5

The segmented copolymer P5 was prepared and purified following themethod used in preparing P1 using the same polymeric initiator asdescribed in Example 1 with the exception of (1) the amount of polymericinitiator and the components for the second step as shown below, and (2)conducting the second step polymerization, initially, at 180° C. untilthe polymer melt was too viscous to stir. Then the stirring wasdiscontinued and polymerization continued in the solid state at 180° C.for 5 hours.

-   -   Polymeric initiator=16.0 g    -   Glycolide=745.4 g (6.4262 mole)    -   ε-Caprolactone=38.6 g (0.3382 mole)    -   Stannous octanoate=0.966 ml of 0.2 M solution in toluene        (1.933×10⁻⁴ mole)        The purified polymer was characterized for its molecular weight        in terms of I.V. in HFIP and T_(m) by DSC, and exhibited an        I.V.=1.3 dL/g and T_(m)=220° C.

Example 6 Synthesis and Characterization of a Typical Fiber-Forming,Segmented, High-Lactide Copolyester, P6

Segmented l-lactide copolyester (P6) was prepared in two steps,purified, and characterized as generally described in U.S. Pat. No.6,342,065 (2002). Briefly, in the first step, a polytrimethylenecarbonate was made as a polymeric initiator by the ring-polymerizationof TMC (58.7 g, 0.575 mole) in the presence of 1,3-propane diol as theinitiator and stannous octanoate as the catalyst at a monomer/initiatorand monomer/catalyst ratios of 150 and 7000, respectively. Thepolymerization was conducted by heating at 165° C. until an essentiallycomplete monomer conversion was realized as determined by GPC (about 2hours). In the second step, the polymeric initiator was cooled to 140°C. and l-lactide (914.3 g, 6.349 mole) and TMC (27.0 g, 0.265 mole) wereadded, mixed by stirring at that temperature until complete melting ofthe solid. The reaction mixture was lowered to 110° C. and an additionalamount of stannous octanoate (2.585 mL of 0.2 M solution in toluene).The reaction temperature was then raised to 140° C. The polymerizationwas allowed to continue while stirring until the polymer melt became tooviscous to stir. The stirring was then stopped and polymerization wascontinued for 60 hours at 140° C. At the conclusion of thepolymerization, the polymer was isolated, ground, dried, and thenpurified by distilling the residual monomer by heating at about 100° C.under reduced pressure. The purified polymer was characterized by itsI.V. using chloroform as a solvent and T_(m) using DSC. The polymerexhibited an I.V.=2.8 dL/g and T_(m)=180° C.

Example 7 General Method for Preparation of Films, F1 and F2 Using P1and P2

A 30-ton Carver Laboratory Press (Model 3895-4 PR1A00) with heatedplaten is used to convert P1 into thin films. The molding processentails placing the ground polymer between two stainless steel platesand heating under pressure at a temperature that is at least 5 degreesabove the polymer melting temperature. The pressure, molding time, andcooling scheme are adjusted to provide the proper film thickness.

Example 8 General Method for Preparation of Multifilament Yarn andConversion to Warp-Knitted Mesh M1 and M2

Conversion of P5 and P6 (from Examples 5 and 6) to multifilament yarns,MF5 and MF6, respectively, was pursued as per the melt-spinning protocoldescribed in U.S. Pat. No. 6,342,065 (2002) using specifically a 43-holedie to produce these multifilaments. The extruded multifilaments werefurther oriented using a one-stage drawing over a heated Godet at about100-120° C. prior to their use for knitted mesh construction. ProcessingMF5 and MF6 to produce warp-knitted meshes, M1 and M2, respectively,entailed warping the yarns onto two beams and constructing the meshesusing a Raschel Knitting Machine equipped with 18-gauge needles. Themeshes were heat-set (or annealed) at 120° C. for one hour. Theresulting meshes were tested for weight/unit area and burst strength.

Example 9 General Method for Preparation of a Typical BicomponentComposite (BC) of a Film and Mesh

The preparation of a bicomponent composite entails heating a typicalfilm (F1 or F1 from Example 7) with a typical mesh (MF1 or MF2 fromExample 8) using a Laboratory Carver Press at temperatures below themesh T_(m), but above the film T_(m).

Example 10 General Method for Preparation of a Typical TricomponentComposite (TC) of a Film, Mesh, and Microfibrous Fabric

The preparation of a typical tricomponent composite (TC) entails theelectrostatic spinning of a solution of a typical microfiber-formingpolymer (P3 or P4 from Examples 3 or 4) onto a typical bicomponentcomposite (BC) from Example 8. The electrostatic spinning process isanalogous to the one described earlier [U.S. Pat. No. 7,416,559 (2008)]for depositing a microfibrous mantle on a metallic stent.

Although the present invention has been described in connection with thepreferred embodiments, it is to be understood that modifications andvariations may be utilized without departing from the principles andscope of the invention, as those skilled in the art will readilyunderstand. Accordingly, such modifications may be practiced within thescope of the following claims. Moreover, Applicant hereby discloses allsubranges of all ranges disclosed herein. These subranges are alsouseful in carrying out the present invention.

What is claimed is:
 1. An absorbable, permeability-modulated barriercomposite comprising: at least three physicochemically distinctcomponents; one component comprising a flexible film having a thicknessof less than 200 microns, the film comprising a synthetic absorbablepolymer, a second component comprising a knitted mesh and a thirdcomponent comprising an electrostatically spun, non-woven microfibrousfabric, and wherein the flexible film is adjoined directly to theknitted mesh which is adjoined directly to the microfibrous fabric toform a three component layered composite; wherein the knitted meshcomprises an absorbable block copolymer comprising a block derived onlyfrom trimethylene carbonate and terminal segments derived fromglycolide; and wherein the flexible film is made of a polyaxialcopolyester derived from at least two monomers selected from the groupconsisting of glycolide, l-lactide, ε-caprolactone, trimethylenecarbonate, p-dioxanone, 1,5-dioxepan-2-one, and a morpholinedione.
 2. Anabsorbable, permeability-modulated barrier composite as in claim 1wherein the electrostatically spun, non-woven fabric is made of apolyaxial copolyester derived from at least two monomers selected fromthe group consisting of glycolide, l-lactide, ε-caprolactone,trimethylene carbonate, p-dioxanone, 1,5-dioxepan-2-one, and amorpholinedione.
 3. An absorbable, permeability-modulated barriercomposite as in claim 1 wherein the electrostatically spun, non-wovenfabric is made of a polyether-ester derived from a polyether-glycolgrafted with at least one monomer selected from the group consisting ofglycolide, l-lactide, ε-caprolactone, trimethylene carbonate,p-dioxanone, 1,5-dioxepan-2-one, and a morpholinedione.
 4. Anabsorbable, permeability-modulated barrier composite as in claim 1wherein at least one of the components comprises at least one bioactiveagent selected from the group consisting of antimicrobial agents,anesthetic agents, anti-inflammatory agents, and tissue growth-promotingagents.
 5. An absorbable, permeability-modulated barrier composite as inclaim 1 wherein at least one of the components comprises ahydroswellable polymer.
 6. An absorbable, permeability-modulated barriercomposite as in claim 5 wherein at least one of the components comprisesat least one bioactive agent selected from the group consisting ofantimicrobial agents, anesthetic agents, anti-inflammatory agents, andtissue growth-promoting agents.
 7. An absorbable, permeability-modulatedbarrier composite comprising: at least three physicochemically distinctcomponents, the first component comprising a flexible film having athickness of less than 400 microns, the film comprising a syntheticabsorbable polymer, the second component comprising an electrostaticallyspun, non-woven microfibrous fabric, and the third component comprisinga knitted mesh, wherein the flexible film is adjoined directly to theknitted mesh and the microfibrous fabric is adjoined directly to theknitted mesh, such that the flexible film and the microfibrous fabricare indirectly joined to each other with the knitted mesh sandwichedtherebetween; wherein the knitted mesh comprises an absorbable copolymerformed from a block derived only from trimethylene carbonate andterminal segments derived from glycolide; and wherein the flexible filmis made of a polyaxial copolyester derived from at least two monomersselected from the group consisting of glycolide, l-lactide,ε-caprolactone, trimethylene carbonate, p-dioxanone, 1,5-dioxepan-2-one,and a morpholinedione.
 8. An absorbable, permeability-modulated barriercomposite as in claim 7 wherein the electrostatically spun, non-wovenfabric is made of a polyaxial copolyester derived from at least twomonomers selected from the group consisting of glycolide, l-lactide,ε-caprolactone, trimethylene carbonate, p-dioxanone, 1,5-dioxepan-2-one,and a morpholinedione.
 9. An absorbable, permeability-modulated barriercomposite as in claim 7 wherein the electrostatically spun, non-wovenfabric is made of a polyether-ester derived from a polyether-glycolgrafted with at least one monomer selected from the group consisting ofglycolide, l-lactide, ε-caprolactone, trimethylene carbonate,p-dioxanone, 1,5-dioxepan-2-one, and a morpholinedione.
 10. Anabsorbable, permeability-modulated barrier composite as in claim 7wherein the knitted mesh comprises a warp-knitted construction and ismade of a polyaxial copolyester derived from at least two monomersselected from the group consisting of glycolide, l-lactide,ε-caprolactone, trimethylene carbonate, p-dioxanone, 1,5-dioxepan-2-one,and a morpholinedione.